WO2021231750A1 - 2'-fucosyllactose pour la prévention et le traitement d'une inflammation induite par un coronavirus - Google Patents

2'-fucosyllactose pour la prévention et le traitement d'une inflammation induite par un coronavirus Download PDF

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Publication number
WO2021231750A1
WO2021231750A1 PCT/US2021/032282 US2021032282W WO2021231750A1 WO 2021231750 A1 WO2021231750 A1 WO 2021231750A1 US 2021032282 W US2021032282 W US 2021032282W WO 2021231750 A1 WO2021231750 A1 WO 2021231750A1
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subject
pathogen
lacto
composition
immune response
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PCT/US2021/032282
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English (en)
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Ardythe L. Morrow
David S. Newburg
John M. Mccoy
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Glycosyn LLC
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Priority to EP21803132.6A priority Critical patent/EP4149482A4/fr
Priority to AU2021271697A priority patent/AU2021271697A1/en
Priority to CA3178736A priority patent/CA3178736A1/fr
Priority to JP2022568917A priority patent/JP2023526271A/ja
Publication of WO2021231750A1 publication Critical patent/WO2021231750A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K35/66—Microorganisms or materials therefrom
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
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    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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    • A61K35/66—Microorganisms or materials therefrom
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics

Definitions

  • the invention provides compositions and methods for utilizing human milk oligosaccharides (hMOS) to prevent and/or treat a pathogenic virus-induced inflammation in a subject.
  • hMOS human milk oligosaccharides
  • Some coronaviruses such as SARS-CoV-2 (COVID-19), are known to bind to the angiotensin-converting enzyme 2 (ACE2) receptor of an animal subject for its infection, which may lead to host inflammation.
  • ACE2 angiotensin-converting enzyme 2
  • the invention is based on the discovery that human milk glycans or human milk oligosaccharides (hMOS) may be used to prevent, attenuate, or treat such infection-related inflammation with at least three beneficial activities, including: 1) preventing viruses, or other respiratory pathogens, from binding to host cells or tissue; 2) reducing host inflammation by, e.g., promoting growth and/or functions of common gut commensal bacteria; and 3) directly reducing host inflammation.
  • beneficial activities including: 1) preventing viruses, or other respiratory pathogens, from binding to host cells or tissue; 2) reducing host inflammation by, e.g., promoting growth and/or functions of common gut commensal bacteria; and 3) directly reducing host inflammation.
  • compositions described hereiln such as human milk oligosaccharides [e.g., 6’-sialyllactose (6’-SL), 3’-sialyllactose (3’-SL), Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), 3-fucosyllactose (3-FL), Lacto-N-fucopentaose I (LNF I), Lacto-N-fucopentaose II (LNF II), Lacto-N-fucopentaose III (LNF III), Lactodifucotetraose (LDFT), Lacto-N-difucohexaose I (LDFH I), Lacto-N- difucohexaose II (LDFH II), Disialyllacto-N-tetraose (DSLNT), 3’-galactosyllact
  • the invention provides methods of using such compositions comprising at least one isolated fucosylation oligosaccharide, such as at least one isolated human milk oligosaccharide (HMO), in an amount effective to prevent, attenuate/reduce, and/or inhibit a respiratory pathogen (such as a coronavirus) infection-related host inflammation and/or to promote recovery from a respiratory pathogen infection-related host inflammaiton in the respiratory system (e.g., lung and bronchi) and/or the gastrointestinal (GI) tract of a subject.
  • the oligosaccharide comprises at least one isolated HMO comprising 2’-fucosyllactose (2’-FL), or combinations with other hMOS described herein.
  • compositions of the invention are administered alone or, alternatively, in conjunction with other agents for preventing, attenuating and/or treating a respiratory pathogen infection.
  • the compositions optionally include a pharmaceutically-acceptable excipient or inactive ingredients.
  • the invention provides a composition comprising at least one isolated human milk oligosaccharide (hMOS) in an amount effective to prevent, attenuate, or treat a pathogen-induced immune response and/or to promote recovery from a pathogen-induced immune response in a subject.
  • the pathogen-induced immune response comprises an inflammation in the lung and/or the GI tract of the subject.
  • the composition comprises at least one isolated human milk oligosaccharide (HMO) comprises 2'-fucosyllactose (2’-FL).
  • the at least one isolated human milk oligosaccharide comprises 2'-fucosyllactose (2’-FL), 6’-sialyllactose (6’- SL), 3’-sialyllactose (3’-SL), Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), 3- fucosyllactose (3-FL), Lacto-N-fucopentaose I (LNF I), Lacto-N-fucopentaose II (LNF II), Lacto-N-fucopentaose III (LNF III), Lactodifucotetraose (LDFT), Lacto-N-difucohexaose I (LDFH I), Lacto-N-difucohexaose II (LDFH II), Disialyllacto-N-tetraose (
  • the composition comprises at least one isolated human milk oligosaccharide (HMO) in an amount effective to prevent, attenuate, or treat a pathogen- induced immune response and/or to promote recovery from a pathogen-induced immune response in a subject, wherein the at least one isolated human milk oligosaccharide (HMO) comprises 2'-fucosyllactose (2’-FL), wherein the pathogen-induced immune response comprises an inflammation in the lung and/or the GI tract of the subject.
  • the composition comprises at least 60%, 75%, 90%, 95%, 98%, or 99% (w/w) of 2’-FL.
  • the composition comprises between 0.01 g 2'-FL and 10 g 2'-FL per 10 grams of composition.
  • the composition i) prevents or reduces pathogen binding to cells of the subject; ii) attenuates the pathogen- induced immune response in the subject; and/or iii) modulating host immune response antagonizing the pathogen-induced immune response in the subject.
  • the composition further comprises an additional agent capable of preventing, attenuating, or treating the pathogen-induced immune response and/or promoting recovery from a pathogen-induced immune response in the subject.
  • the additional agent comprises at least one of 6’-sialyllactose (6’-SL), 3’- sialyllactose (3’-SL), Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), 3-fucosyllactose (3-FL), Lacto-N-fucopentaose I (LNF I), Lacto-N-fucopentaose II (LNF II), Lacto-N- fucopentaose III (LNF III), Lactodifucotetraose (LDFT), Lacto-N-difucohexaose I (LDFH I), Lacto-N-difucohexaose II (LDFT), Lacto-N-
  • the additional agent comprises at least one of non-HMO prebiotic agents, such as galacto- oligosaccharides (GOS) or fructo-oligosaccharides (FOS), at least one probiotic bacterium (e.g., bacterium of the genera Bifidobacterium, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Enterococcus, Streptococcus, Bacteroides, Parabacteroides, Prevotella or Clostridium), and/or at least one agent selected from the group consisting of antibiotics or anti-viral compounds, anti-inflammatory compounds, natural or synthetic corticosteroids, cortisone, hydrocortisone, bethamethasone, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, naproxen, indom
  • the composition described herein is in the form of a powder, a tablet, an aerosol, feed for mammalian animals, a packet of sugar, yogurt, a beverage, a weaning food, or an infant formula.
  • the respiratory pathogen comprises a virus.
  • the virus may comprise i) a coronavirus; ii) a severe acute respiratory syndrome virus (SARS-CoV); iii) a SARS-CoV-2 (COVID-19) virus; and/or iv) a Middle East respiratory syndrome coronavirus (MERS-Cov).
  • the virus binds to the ACE2 receptor on the animal cell or tissue.
  • the binding between the virus and the animal cell or tissue is mediated by fucosylation on the animal cell or tissue, such as at least one fucosylated oligosaccharide or one fucosylated polypeptide or protein.
  • the animal cell or tissue described herein comprises a tissue of an animal respiratory system (e.g., lung and bronchi) or the gastrointestinal (GI) tract mucosa or a cell in such tissue.
  • an animal respiratory tissue may include a tissue from at least one of the lung or the upper respiratory tract (including, e.g., nose, nasal cavities, sinuses, pharynx and the part of the larynx above the vocal folds) or the lower tract (including, e.g., the lower part of the larynx, the trachea, bronchi, bronchioles and the alveoli).
  • the upper respiratory tract including, e.g., nose, nasal cavities, sinuses, pharynx and the part of the larynx above the vocal folds
  • the lower tract including, e.g., the lower part of the larynx, the trachea, bronchi, bronchioles and the alveoli.
  • the animal cell or tissue described herein expresses a fucosyltransferase 2 (FIJT2 ) genotype.
  • FIJT2 fucosyltransferase 2
  • the subject is a human, non-human primate, mouse, rat, dog, cat, horse, cattle, sheep, pig, chicken, or goat. In some embodiments, the subject is an infant, a child, an adult, and/or an elder.
  • the subject has, is prone to have, or is specifically sensitive or vulnerable to, a disease or disorder selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), respiratory failure, impaired lung function, hypoxemia, systemic organ failure, infectious diarrhea, antibiotic-associated diarrhea, traveler’s diarrhea, necrotizing enterocolitis, inflammatory bowel disease, and an allergy inflammation.
  • ARDS acute respiratory distress syndrome
  • the invention provides a use of the composition described herein for preparation of a medicament for preventing, attenuating, or treating a pathogen-induced immune response and/or promoting recovery from a pathogen-induced immune response in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one isolated human milk oligosaccharide (HMO) comprising 2'-fucosyllactose (2’-FL).
  • HMO human milk oligosaccharide
  • the invention provides a method of preventing, attenuating, or treating a pathogen-induced immune response and/or promoting recovery from a pathogen- induced immune response in a subject, comprising administering to the subject a pharmaceutically effective amount of at least one isolated human milk oligosaccharide (HMO) comprising 2'-fucosyllactose (2’-FL).
  • HMO human milk oligosaccharide
  • the at least one isolated HMO comprises at least 60%, 75%, 90%, 95%, 98%, or 99% (w/w) of 2’-FL.
  • the pharmaceutically effective amount is equivalent to a dosage of i) about 0.2 g to 10 g per day; ii) about 1 g to 10 g per day; and/or ii) about 5 g to 10 g per day.
  • the at least one isolated HMO is administered to the lung and/or the GI tract of the subject.
  • the method described herein further comprises administering a pharmaceutically effective amount of an additional agent capable of preventing, attenuating, or treating the pathogen-induced immune response and/or promoting recovery from a pathogen-induced immune response to the subject.
  • the additional agent comprises at least one of 6’-sialyllactose (6’-SL), 3’-sialyllactose (3’-SL), Lacto-N- tetraose (LNT), Lacto-N-neotetraose (LNnT), 3-fucosyllactose (3-FL), Lacto-N-fucopentaose I (LNF I), Lacto-N-fucopentaose II (LNF II), Lacto-N-fucopentaose III (LNF III), Lactodifucotetraose (LDFT), Lacto-N-difucohexaose I (LDFH I), Lacto-
  • the additional agent comprises at least one of non-HMO prebiotic agents, such as galacto- oligosaccharides (GOS) or fructo-oligosaccharides (FOS), at least one probiotic bacterium (e.g., bacterium of the genera Bifidobacterium, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Enterococcus, Streptococcus, Bacteroides, Parabacteroides, Prevotella or Clostridium), and/or at least one agent selected from the group consisting of antibiotics or anti-viral compounds, anti-inflammatory compounds, natural or synthetic corticosteroids, cortisone, hydrocortisone, bethamethasone, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, naproxen, indom
  • the pathogen comprises a virus comprising i) a coronavirus; ii) a COVID-19 virus; iii) a severe acute respiratory syndrome virus (SARS-CoV); and/or iv) a MERS-CoV.
  • a virus comprising i) a coronavirus; ii) a COVID-19 virus; iii) a severe acute respiratory syndrome virus (SARS-CoV); and/or iv) a MERS-CoV.
  • the subject is a human, a non-human primate, mouse, rat, dog, cat, horse, cattle, sheep, pig, chicken, or goat.
  • the subject has, is prone to have, or is specifically sensitive or vulnerable to, a disease or disorder selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), respiratory failure, impaired lung function, hypoxemia, systemic organ failure, infectious diarrhea, antibiotic-associated diarrhea, traveler’s diarrhea, necrotizing enterocolitis, inflammatory bowel disease, and an allergy inflammation.
  • ARDS acute respiratory distress syndrome
  • the method described herein comprising administering the composition to the respiratory system (e.g., lung and bronchi) or the gastrointestinal (GI) tract mucosa of the subject.
  • the at least one isolated HMO described herein is administered to the subject through an acceptable routes, such as inhalation, pulmonary lavage, oral ingestion, anal administration, and/or injection.
  • the pharmaceutically effective amount for the at least one isolated HMO described herein is equivalent to a dosage of i) about 0.2 g to 10 g per day; ii) about 1 g to 10 g per day; and/or ii) about 5 g to 10 g per day.
  • the pharmaceutically effective amount for the at least one isolated HMO described herein is equivalent to a dosage of about 0.2 g to about 10 g per day, about 0.5 g to about 10 g per day, about 1 g to about 10 g per day, about 1 g to about 5 g per day, about 5 g to about 10 g per day, or any dosages found effective to the specific subject.
  • an “isolated” or “purified” oligosaccharide is substantially free of other oligosaccharides, with which it naturally occurs in human milk. Purified oligosaccharides are also free of cellular material when produced biosynthetically, or other chemicals when chemically synthesized. Purified compounds are at least 50% or 60% (by dry weight) of the compound of interest.
  • the preparation is at least 70%, 75%, 80%, 85%, 90%,
  • a purified oligosaccharide e.g., 2’-FL, 3-FL, LDFT, or others described herein, is one that is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, or 100% (w/w) of the desired oligosaccharide by weight.
  • Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography, or high-performance liquid chromatography (HPLC) analysis.
  • oligosaccharides are purified and used in a number of products for consumption by humans as well as animals, such as companion animals (dogs, cats) as well as livestock (bovine, equine, ovine, caprine, or porcine animals, as well as poultry). “Purified” also defines a degree of sterility that is safe for administration to a human subject, e.g., lacking infectious or toxic agents.
  • substantially pure an oligosaccharide that has been separated from the components that naturally accompany it.
  • the oligosaccharide is substantially pure when it is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or even more, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated.
  • the mean ratio of 2’-FL:3FL:LDFT in human milk is 5.65:2: 1.
  • compositions comprising more than one isolated oligosaccharide, e.g., a composition comprising two isolated oligosaccharides
  • the first oligosaccharide e.g., 2’-FL, 3-FL, or LDFT
  • the second oligosaccharide may be mixed in any ratio described herein.
  • the composition comprises the first purified oligosaccharide (e.g., 2’-FL, 3-FL, or LDFT) and the second oligosaccharide in a ratio of, e.g., 1:1, 1:2, 1:5, 1:10, 1:100, 100:1, 10:1, 5:1, or 2:1, or any other ratio suitable to obtain prebiotic effects.
  • the subject is pre-treated with at least one agent for preventing the respirtory pathogen infection (e.g., an antibiotic).
  • antibiotics may include, for example, at least one of Kanamycin, Gentamicin, Colistin, Metronidazole, Vancomycin, or any such agents or antibiotics known by a skilled artisan with such function.
  • the at least one isolated HMO attenuates the respirtory pathogen infection, measurable by, e.g., pathogen colonization and/or adhesiveness, to cells or tissue of the subject.
  • the at least one isolated HMO attenuates the pathogen infection, e.g., the pathogen colonization and/or adhesiveness to cells or tissue of the subject by at least 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more.
  • the at least one isolated HMO described herein may comprise 2’-FL, 3-FL, 6’-SL, 3’- SL, LNFPI, TFiLNO, or other oligosaccharides.
  • the at least one isolated HMO comprises 2’-FL.
  • the at least one isolated HMO is at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more pure (in, e.g., w/w).
  • the concentration by weight of the at least one isolated HMO in the composition is i) from about 1% to about 99%; ii) from about 10% to about 90%; iii) from about 30% to about 70%; iv) from about 40% to about 60%; or v) about 50% .
  • composition described herein may include a 2 nd , 3 rd , 4 th ,
  • the composition described herein comprises between 0.01 g and 10 g of the first purified oligosaccharide, e.g., 2’-FL, 3-FL, LDFT, or others described herein, per 10 grams of composition.
  • the composition comprises between 0.1 g and 5 g, between 0.5 g and 5 g, between 1 g and 5 g, or between 1.5 g and 3 g of the at least one isolated oligosaccharide, e.g., 2’-FL, 3-FL, LDFT, or others described herein, per 10 grams of composition.
  • the composition comprises between 0.01 g and 1 g of the at least one isolated oligosaccharide per gram of composition.
  • the composition comprises between 0.01 g 2’-FL and 1 g 2’-FL per gram of composition.
  • the composition described herein comprises a second oligosaccharide, in addition to the at least one isolated oligosaccharide in the composition.
  • the second oligosaccharide is a purified human milk oligosaccharide.
  • the second oligosaccharide is not a human milk oligosaccharide.
  • the second oligosaccharide comprises fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), or lactulose.
  • the second oligosaccharide comprises galacto-oligosaccharides (GOS).
  • the subject described herein may be a mammal.
  • the subject is a human.
  • the subject is a non-human mammal.
  • the subject is a pre-term infant, a term infant, a child, an adolescent, or an elder.
  • composition described herein is in the form of a tablet, a capsule, a powder, a beverage, or an infant formula.
  • the at least one isolated oligosaccharide (such as HMO) of the invention are in the form of powdered/dry milk.
  • infant is meant a child under the age of 12 months.
  • infant formula is meant a foodstuff intended for particular nutritional use by infants aged under twelve months and constituting the principal liquid element in the progressively diversified diet of this category of person.
  • the composition described herein is provided in dry milk, in mashed rice, in a banana, in a porridge, or in a gruel.
  • the HMOS of the invention are added to weaning foods (e.g., mashed rice, bananas, porridges and other gruels, formula, etc.) to reduce or ameliorate these diseases.
  • weaning foods e.g., mashed rice, bananas, porridges and other gruels, formula, etc.
  • the HMOS described herein are added to the weaning foods during the manufacturing process.
  • the HMOS are added to the weaning foods after the manufacturing process, but prior to ingestion. For example, packets of sugars including one or more isolated or purified HMOS are added to weaning foods prior to infant ingestion.
  • composition described herein may be also added to other consumable products such as yogurt or probiotic beverages for consumption by infants, children, and adults.
  • the composition may be added to powdered/dry milk.
  • composition described herein may be administered to the subject locally or systemically through other viable routes to the respiratory system or the GI tract.
  • treating and “treatment” as used herein refer to the administration of an agent or formulation to a clinically symptomatic individual afflicted with an adverse condition, disorder, or disease, so as to effect a reduction in severity and/or frequency of symptoms, eliminate the symptoms and/or their underlying cause, and/or facilitate improvement or remediation of damage.
  • preventing and “prevention” refer to the administration of an agent or composition to a clinically asymptomatic individual who is susceptible to a particular adverse condition, disorder, or disease, and thus relates to the prevention of the occurrence of symptoms and/or their underlying cause.
  • an effective amount is meant an amount of an oligosaccharide to prevent, attenuate, and/or inhibit, a respiratory pathogen- induced host inflammation in a subject, or to treat a respiratory pathogen-induced host inflammation in a subject.
  • an effective amount is meant an amount of an oligosaccharide to prevent, attenuate, and/or inhibit, a respiratory pathogen- induced host inflammation in a subject, or to treat a respiratory pathogen-induced host inflammation in a subject.
  • the attending physician or veterinarian decides the appropriate amount and dosage regimen.
  • transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim.
  • the transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
  • Some respiratory pathogens such as coronaviruses, infect millions of people and cause enormous mobility and mortality.
  • compositions that contain at least one fucosylated oligosaccharide, such as at least one isolated human milk oligosaccharide (hMOS), in an amount effective to prevent, ahenuate/reduece, and/or inhibit a respiratory pathogen infection-induced inflammation and/or to promote recovery from the pathogen infection- induced inflammation in the respiratory system and/or the GI tract of a subject.
  • fucosylated oligosaccharides include, e.g., 2’-fucosyllactose (2’-FL), 3-fucosyllactose (3-FL), lactodifucotetraose (LDFT), and others described herein.
  • compositions described herein prevent, ahenuate, and/or inhibit the binding, and thus the entry for infection, of the pathogen (or other pathogens) to a cell or tissue of the respiratory system and/or the GI tract of the subject, promoting growth and/or functions of common gut commensal bacteria, and/or directly regulating (e.g., reducing) host immune responses.
  • the binding and/or the infection require fucosylation on the cell or tissue, while the compositions described herein compete with endogenous receptors for the pathogen (or other pathogens) to bind the pathogen (or other pathogens), thus preventing, attenuating or inhibiting the pathogen (or other pathogens) from binding to the cell or tissue and causing infection.
  • At least one isolated human milk oligosaccharide is administrated in an amount effective to prevent, attenuate or inhibit a respiratory pathogen (e.g., a coronavirus) infection-induced host inflammation and/or to promote recovery from a respiratory pathogen infection-induced host inflammation in the respiratory system and/or the gastrointestinal (GI) tract of a subject.
  • a respiratory pathogen e.g., a coronavirus
  • At least one isolated and/or purified 2’-FL, 3-FL, LDFT, or other hMOS is administered to selectively prevent, attenuate or inhibit binding of the pathogen to its receptor in the respiratory system and/or the GI tract of the subject, to improve growth and/or functions of common gut commensal bacteria, and/or to directly regulate (e.g., reduce) host immune responses.
  • pathogens may infect the respiratory system and/or the GI tract of a subject described herein.
  • SARS-CoV, SARS-CoV-2, and hCoV-NL63 are known respiratory pathogens.
  • Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is caused also by certain other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19. Symptoms in other species vary: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea. SARS-CoV-2/COVID-19
  • SARS-CoV-2 severe acute respiratory syndrome virus
  • ARDS [Matthay, M.A., et ak, Acute respiratory distress syndrome. Nat Rev Dis Primers, 2019. 5(1): p. 18.] is characterized by an acute progressive inflammatory reaction in the lungs, which in the case of COVID-19 is brought on by the ongoing SARS-CoV-2 infection.
  • the lung inflammatory reaction in response to infection leads to excessive fluid build-up, with consequent impaired pulmonary function and hypoxemia.
  • Ongoing neutrophil and T-lymphocyte infiltration into the infected lung tissue amplifies the inflammation which can lead to a “cytokine storm”, i.e. an uncontrolled release of proinflammatory cytokines, leading to profound pulmonary damage, systemic organ failure, and death.
  • the SARS-CoV-2 virus is novel and much remains unknown about its biology. Prevention and treatment strategies for COVID-19 are in their infancy, with many ongoing approaches [Knip, M. and J. Honkanen, Modulation of Type 1 Diabetes Risk by the Intestinal Microbiome. Curr Diab Rep, 2017. 17(11): p. 105] aimed at preventing or reducing the incidence and extent of SARS-CoV-2 infection, e.g. through the development of SARS-CoV- 2 vaccines [Chen, W.H., et ak, The SARS-CoV-2 Vaccine Pipeline: an Overview. Curr Prop Med Rep, 2020: p.
  • SARS-CoV-2 -targeted anti-viral agents [Sheahan, T.P., et ak, An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus. bioRxiv, 2020]
  • SARS-CoV-2 -targeted anti-viral agents Sheahan, T.P., et ak, An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus. bioRxiv, 2020]
  • additional approaches aimed at preventing or mitigating the damaging inflammatory reaction which causes much of the serious morbidity and mortality associated with COVID-19.
  • the human immune system is extremely sensitive to the presence of microbial and viral pathogens, and possesses highly-evolved innate and acquired mechanisms for recognizing molecular signatures of infection, such as the presence of bacterial cell wall components, bacterial and viral nucleic acid fragments, or specific pathogen antigens seen previously in prior infections.
  • the immune system is also powerfully triggered by the presence of dead or dying infected host cells.
  • the gut microbiota has also been linked to the functioning of distal organ systems, and gut dysbiosis has been tied into many diseases, including many with systemic inflammatory involvement.
  • inflammatory arthritis Rostier, R., et al., Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis. Sci Rep, 2017. 7(1): p. 15613
  • atherosclerosis [Brandsma, E., et al., A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis. CircRes, 2019. 124(1): p. 94-100; Bogiatzi, C., et al., Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis, 2018. 273: p.
  • lupus (Azzouz, D., et al., Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal. Ann Rheum Dis, 2019), multiple sclerosis (Ochoa-Reparaz, J., et al., A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol, 2010. 3(5): p. 487-95; Chu, F., et al., Gut Microbiota in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis: Current Applications and Future Perspectives. Mediators Inflamm, 2018. 2018: p.
  • hMOS Human milk oligosaccharides
  • hMOS are absorbed poorly by the infant gut wall [Chaturvedi, P., et al., Survival of human milk oligosaccharides in the intestine of infants . Adv Exp Med Biol, 2001. 501: p. 315-23] and are consequently the majority are retained in the gut lumen, where they are utilized by the resident microbiota as a carbon source for growth (i.e. hMOS are natural human prebiotics) [Yu, Z.-T., et al., The Principal Fucosylated Oligosaccharides of Human Milk Exhibit Prebiotic Properties on Cultured Infant Microbiota. Glycobiology, 2012. 23(2): p.
  • 2’-fucosyllactose (2’-FL) is one of the simplest hMOS, being a trisaccharide with an a(l,2)-linked fucose bound to the galactose moiety of lactose (Bode 2012).
  • 2’-FL is, by far, the most abundant single hMOS component in the milk of most mothers, representing approximately 25% of the total oligosaccharide content by weight.
  • 2’-FL is perhaps the most well-studied, and was the first hMOS molecule produced in bulk for inclusion in infant formula and foodstuffs. 2’-FL may have three broad classes of beneficial activities towards host inflammation induced by respiratory pathogen infection:
  • a(l,2)-fucose-conjugated glycans on epithelial surfaces are well established as being binding sites for a variety of pathogens, principally in the gut.
  • Campylobacter jejuni, Salmonella typhimurium, Helicobacter pylori, enterotoxigenic Escherichia coli, Vibrio cholerae, andNorovirus all bind to a(l,2)-fucose-conjugated epithelial glycans at the first step in infection [Pickard, J.M. and A.V. Chervonsky, Intestinal fucose as a mediator of host-microbe symbiosis. J Immunol, 2015.
  • 2’- FL comprises an a(l,2)-linked fucose moiety, and has been shown to act as a soluble “decoy” molecule (competitive inhibitor) that can effectively prevent pathogen binding [Ruiz- Palacios, G.M., et ak, Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. JBiol Chem, 2003. 278(16): p.
  • 2’-FL is a prebiotic sugar that is efficiently utilized for growth by common gut commensal bacteria such as the Bifidobacteria and the Bacteroides (Yu et al., 2012; Yu et al., 2013).
  • Certain gut commensals that grow on 2’-FL e.g. Bacteroides fragilis
  • have also been shown to possess mechanisms for down-regulating inflammation in the gut (Mazmanian et al., 2008; Kasper et al., 2009; Troy and Kasper, 2010; Surana and Kasper, 2012) (i.e., 2’-FL has an indirect anti-inflammatory activity that is mediated by the gut microbiota); and
  • 2’-FL has been shown to have direct effects on immune function [He, Y., et al., The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut, 2016. 65(1): p. 33-46; Sodhi, C.P., et al., The human milk oligosaccharides 2’-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling. Pediatric Research, 2020: p. 1-13; He, Y., N.T. Lawlor, and D.S. Newburg,
  • 2’-FL has been shown to have a direct anti-inflammatory activity, and, moreover, exhibits an indirect anti-inflammatory activity mediated by the microbiota. Modulating the microbiota has previously been shown to have impacts on systemic inflammation in multiple disease scenarios.
  • the present invention envisages the use of 2’-FL as an agent to prevent or reduce the inflammation (principally in the lungs) caused by SARS-CoV-2 infection.
  • 2’-FL may be administered orally, either by itself in tablet or powder form, or it may be conveniently dissolved in a little water or other beverage, or it may be included in foodstuffs or in food or medical supplements.
  • the preferred 2’-FL adult dose is 5 g per day, but anywhere between 0.2 g per day up to 10 g per day may be taken.
  • 2’-FL is a natural component of human milk and as such it is non-toxic, however high doses (i.e. >10 g per day) may lead to mild gut discomfort and a reversible osmotic diarrhea. 2’-FL may be taken at the onset of COVID-19 symptoms, or may be safely taken daily as a prophylactic during times when COVID-19 is prevalent in populations.
  • 2’-FL may be combined with other agents, for example other human milk oligosaccharides that may exhibit direct or indirect anti-inflammatory actions may synergize with, or add to, the anti-inflammatory actions of 2’-FL.
  • additional hMOS which could be used in combination with 2’-FL include, but are not limited to: 6’-sialyllactose (6’- SL), 3’-sialyllactose (3’-SL), Lacto-N-tetraose (LNT), Lacto-N-neotetraose (LNnT), 3- fucosyllactose (3-FL), Lacto-N-fucopentaose I (LNF I), Lacto-N-fucopentaose II (LNF II), Lacto-N-fucopentaose III (LNF III), Lactodifucotetraose (LDFT), Lacto-N-difucohexaose I (LDF
  • non-hMOS prebiotics such as mixtures of synthetic galacto-oligosaccharides (GOS) or fructo-oligosaccharides (FOS) could be utilized in combination with 2’-FL to treat coronavirus-induced inflammation.
  • GOS galacto-oligosaccharides
  • FOS fructo-oligosaccharides
  • antibiotics or anti-viral compounds may also be used in combination with 2’-FL in treating coronavirus-induced inflammation, for example antibiotics or anti-viral compounds, or other anti-inflammatory compounds such as natural or synthetic corticosteroids (e.g. cortisone, hydrocortisone, bethamethasone, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone), NSAIDs (nonsteroidal anti-inflammatory drugs, e.g. ibuprofen, naproxen, indomethacin, oxaprozin, etodolac, nabumetone, diclofenac, vimovo), and other anti-pyretics (e.g. paracetamol, aspirin, acetaminophen).
  • corticosteroids e.g. cortisone, hydrocortisone, bethamethasone, prednisone, prednisolone,
  • 2’-FL may also be used to combat inflammation resulting from SARS-CoV-2 infection in combination with pre-, co- or post-administered probiotic organisms, for example with probiotic bacteria of the genera Bifidobacterium, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Enterococcus, Streptococcus, Bacteroides, Parabacteroides, Prevotella or Clostridium. 2’-FL may also be utilized to treat the inflammation resulting from infections of other coronaviruses, e.g. SARS-CoV and MERS-CoV, or other viruses causing pulmonary inflammation.
  • other coronaviruses e.g. SARS-CoV and MERS-CoV
  • compositions may be used to deliver the fucosylated oligosaccharides (such as HMOS) described herein to a subject.
  • the fucosylated oligosaccharides may be administered locally or systemically to a subject, including administering to, e.g., the respiratory system and/or the GI tract of the subject, via, e.g., inhalation, pulmonary lavage, oral ingestion, anal administration, infusion, and/or injection.
  • Administration routes also include, but not limited to, administering to a subject intravenously, intradermally, intraperitoneally, intrapleurally, intratracheally, intramuscularly, subcutaneously, by injection, and by infusion.

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Abstract

L'invention concerne des compositions et des procédés d'utilisation d'oligosaccharides, tels que des oligosaccharides de lait humain isolés, pour atténuer une inflammation hôte induite par une infection par un pathogène respiratoire et/ou pour favoriser la récupération à partir d'une inflammation hôte induite par une infection par un pathogène respiratoire chez un sujet.
PCT/US2021/032282 2020-05-13 2021-05-13 2'-fucosyllactose pour la prévention et le traitement d'une inflammation induite par un coronavirus WO2021231750A1 (fr)

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AU2021271697A AU2021271697A1 (en) 2020-05-13 2021-05-13 2'-fucosyllactose for the prevention and treatment of coronavirus-induced inflammation
CA3178736A CA3178736A1 (fr) 2020-05-13 2021-05-13 2'-fucosyllactose pour la prevention et le traitement d'une inflammation induite par un coronavirus
JP2022568917A JP2023526271A (ja) 2020-05-13 2021-05-13 コロナウイルスによって誘導される炎症の防止および処置のための２’－フコシルラクトース

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